Nanomaterials are increasingly being utilized for biomedical applications as therapeutics and drug delivery systems. Following their introduction into a physiological environment they rapidly associate a variety of macromolecules forming a corona. This corona modifies the size and interactive interface of the nanomaterial resulting in altered bio distribution, clearance, activity, and toxicity. The composition of the corona is dependent on the physicochemical properties of the nanomaterial, as well as, the physiological environment. To date most evaluation of nanomaterial toxicity is performed under normal, healthy conditions. However, due to the vast and growing portion of our population that suffer from chronic conditions such as obesity and cardiovascular diseases these nanomaterials will not be introduced into healthy physiological environments. In this proposal we hypothesize that an underlying condition known to alter serum protein and lipid content, hyperlipidemia, will modify the corona that forms on nanomaterials as will different sizes and therapeutic surface coatings. Further we will examine how these modifications in coronal composition influence cellular uptake, in vivo bio distribution, subcellular localization, intracellular fate, and toxiciy. To test this hypothesis we will utilize iron oxide nanoparticles, which are currently in development for biomedical applications including their use as MRI contrast agents and silver nanoparticles, which are being used for their antimicrobial/fungal properties. Cellular interactions and toxicological effects will be examined in macrophages and endothelial cells to represent two key cell types that will interact with nanomaterials and are critical in inflammation and vascular biology. Ultimately, through a thorough understanding of the corona and its biological consequences gained from this proposal, we can develop effective nanotherapeutics with limited toxicological implications.